Human defensins and cytokines in vaginal lavage fluid of women with bacterial vaginosis

Fan, Shang­rong; Liu, X.P.; Liao, Qinping

doi:10.1016/j.ijgo.2008.05.020

Cited by 58 publications

(54 citation statements)

References 25 publications

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“…In PMN granules, ␣-defensins attain mg per ml concentrations (30); however, AP concentrations likely decline significantly upon release into the extracellular milieu, where H. ducreyi is most likely to encounter the APs. Estimates of extracellular AP concentrations in human tissues vary extensively among studies, with vaginal concentrations of HNP-1 to -3 ranging from 0.2 g per ml (45) to 3 g per ml (5) and an estimated 60 to 110 g of HD5 per ml (18); urethral concentrations of HD5 were estimated at 0.5 to 18 g per ml (38). The concentration range used in our assays covers most estimates of physiologically relevant doses.…”

Section: Discussionmentioning

confidence: 99%

Deletion of mtrC in Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon

Rinker

Trombley

et al. 2011

Infect Immun

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Haemophilus ducreyi resists killing by antimicrobial peptides encountered during human infection, including cathelicidin LL-37, ␣-defensins, and ␤-defensins. In this study, we examined the role of the proton motive force-dependent multiple transferable resistance (MTR) transporter in antimicrobial peptide resistance in H. ducreyi. We found a proton motive force-dependent effect on H. ducreyi's resistance to LL-37 and ␤-defensin HBD-3, but not ␣-defensin HNP-2. Deletion of the membrane fusion protein MtrC rendered H. ducreyi more sensitive to LL-37 and human ␤-defensins but had relatively little effect on ␣-defensin resistance. The mtrC mutant 35000HPmtrC exhibited phenotypic changes in outer membrane protein profiles, colony morphology, and serum sensitivity, which were restored to wild type by trans-complementation with mtrC. Similar phenotypes were reported in a cpxA mutant; activation of the two-component CpxRA regulator was confirmed by showing transcriptional effects on CpxRA-regulated genes in 35000HPmtrC. A cpxR mutant had wild-type levels of antimicrobial peptide resistance; a cpxA mutation had little effect on defensin resistance but led to increased sensitivity to LL-37. 35000HPmtrC was more sensitive than the cpxA mutant to LL-37, indicating that MTR contributed to LL-37 resistance independent of the CpxRA regulon. The CpxRA regulon did not affect proton motive force-dependent antimicrobial peptide resistance; however, 35000HPmtrC had lost proton motive force-dependent peptide resistance, suggesting that the MTR transporter promotes proton motive forcedependent resistance to LL-37 and human ␤-defensins. This is the first report of a ␤-defensin resistance mechanism in H. ducreyi and shows that LL-37 resistance in H. ducreyi is multifactorial.

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Section: Discussionmentioning

confidence: 99%

Deletion of mtrC in Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon

Rinker

Trombley

et al. 2011

Infect Immun

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“…They are divided into two classes, ␣-and ␤-defensins, based on the pattern of disulfide bonds that stabilize their tertiary structure (1,2). HD5 is one of six human ␣-defensins and is constitutively expressed and secreted in the female and male genitourinary tracts (3)(4)(5). Concentrations of HD5 in vaginal lavage fluid of healthy women have been reported to be 16.5 Ϯ 10.5 M (3).…”

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confidence: 99%

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

Wiens

Smith

2015

J Virol

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Human papillomavirus (HPV) is a significant oncogenic virus, but the innate immune response to HPV is poorly understood. Human ␣-defensin 5 (HD5) is an innate immune effector peptide secreted by epithelial cells in the genitourinary tract. HD5 is broadly antimicrobial, exhibiting potent antiviral activity against HPV at physiologic concentrations; however, the specific mechanism of HD5-mediated inhibition against HPV is unknown. During infection, the HPV capsid undergoes several critical cell-mediated viral protein processing steps, including unfolding and cleavage of the minor capsid protein L2 by host cyclophilin B and furin. Using HPV16 pseudovirus, we show that HD5 interacts directly with the virus and inhibits the furin-mediated cleavage of L2 at the cell surface during infection at a step downstream of the cyclophilin B-mediated unfolding of L2. Importantly, HD5 does not affect the enzymatic activity of furin directly. Thus, our data support a model in which HD5 prevents furin from accessing L2 by occluding the furin cleavage site via direct binding to the viral capsid. IMPORTANCEOur study elucidates a new antiviral action for ␣-defensins against nonenveloped viruses in which HD5 directly interferes with a critical host-mediated viral processing step, furin cleavage of L2, at the cell surface. Blocking this key event has deleterious effects on the intracellular steps of virus infection. Thus, in addition to informing the antiviral mechanisms of ␣-defensins, our studies highlight the critical role of furin cleavage in HPV entry. Innate immune control, mediated in part by ␣-defensins expressed in the genital mucosa, may influence susceptibility to HPV infections that lead to cervical cancer. Moreover, understanding the mechanism of these natural antivirals may inform the design of therapeutics to limit HPV infection. Defensins are effector peptides of the human innate immune system. They are divided into two classes, ␣-and ␤-defensins, based on the pattern of disulfide bonds that stabilize their tertiary structure (1, 2). HD5 is one of six human ␣-defensins and is constitutively expressed and secreted in the female and male genitourinary tracts (3-5). Concentrations of HD5 in vaginal lavage fluid of healthy women have been reported to be 16.5 Ϯ 10.5 M (3). Although originally discovered due to their antibacterial activity, defensin antiviral activity against both enveloped and nonenveloped viruses has also been described. Neutralization of enveloped viruses, such as human immunodeficiency virus 1 (HIV-1), herpes simplex virus (HSV), and respiratory syncytial virus (RSV), is largely dependent on direct interactions of defensins with both viral attachment proteins and cellular receptors, as well as envelope damage, fusion inhibition, and modulation of host responses (6). Inhibition of these viruses may be due to multiple defensin actions rather than a single overriding inhibitory mechanism. While less is known about the mechanisms of defensin antiviral activity against nonenveloped viruses, human adeno...

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“…Sexually transmitted infections (STIs) increase the risk of HIV mucosal transmission in part by altering epithelial barriers (10,16,24). Individuals with STIs exhibit elevated levels of antimicrobial peptides, including human defensin 5 (HD5) produced by genital epithelial cells and human neutrophil peptides (HNPs) produced by infiltrating neutrophils (9,27,30,35). These defensins are believed to play a role in controlling bacterial infection.…”

mentioning

confidence: 99%

Human Alpha-Defensin HNP1 Increases HIV Traversal of the Epithelial Barrier: A Potential Role in STI-Mediated Enhancement of HIV Transmission

et al. 2015

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Alpha-defensins, including human neutrophil peptides 1-3 (HNP1-3) and human defensin 5 (HD5), are elevated at the genital mucosa in individuals with sexually transmitted infections (STIs). The presence of STIs is associated with an increased risk of human immunodeficiency virus (HIV) transmission, suggesting there may be a role for defensins in early events of HIV transmission. HD5 has been demonstrated to contribute to STImediated increased HIV infectivity in vitro. HNPs exhibit anti-HIV activity in vitro. However, increased levels of HNPs have been associated with enhanced HIV acquisition and higher viral load in breast milk. This study found that HNP1, but not HD5, significantly disrupted epithelial integrity and promoted HIV traversal of epithelial barriers. Linear HNP1 with the same charges did not affect epithelial permeability, indicating that the observed effect of HNP1 on the epithelial barrier was structure dependent. These results suggest a role for HNP1 in STI-mediated enhancement of HIV transmission.

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Human defensins and cytokines in vaginal lavage fluid of women with bacterial vaginosis

Abstract: HBD-2 and HD-5 may be involved in defending against invasion by BV-related microorganisms and the decrease in IL-4 concentration may increase susceptibility to BV.

Cited by 58 publications

References 25 publications

Deletion of mtrC in Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon

Deletion of mtrC in Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon

Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

Human Alpha-Defensin HNP1 Increases HIV Traversal of the Epithelial Barrier: A Potential Role in STI-Mediated Enhancement of HIV Transmission

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